N-substituted 1,2,3,4,4alpha,10alpha-hexahydro-(10h)-1-benzopyrano-(3,2,c)-pyridines

ABSTRACT

The compounds are N-substituted 4a-oxy-1,2,3,4,-4a,10ahexahydro-(10H)-1-benzopyrano-(3,2-c)-pyridines, useful as sedatives and antiphlogistics in warm-blooded animals.

United States Patent Ohnacker et al.

[ N-SUBSTITUTED l,2,3,4,4a,10a-

HEXAHYDRO-(l0H)-l-BENZOPYRANO- [3,2,C ]-PYRIDINES [72] Inventors: Gerhard Olmacker; l'lelmut Daniel; Hans Machleidt, all of Biberach,

Germany [73] Assignee: Boehringer lngelheim G.m.b.ll.,

lngelheim/Rhein, Germany [22] Filed: June 20,1968

[21 Appl. No.: 738,398

[30] Foreign Application Priority Data June 21, l967 Germany ..T 34142 [52] US. Cl. ..260/293.55, 424/267, 260/296 R, 260/570.9, 260/293.89, 260/293.65, 260/293.8, 260/293.86, 260/293.76 [51] Int. Cl. ..C07d 39/00 51 Sept. 12, 1972 Primary Examiner-Henry R. Jiles Assistant Examiner-S. D. Winters Attorney-Hammond & Littell [57] ABSTRACT The compounds are N-substituted 4a-oxy-l,2,3,4, 4a, 1 0a-hexahydro-( l0l-l)-1-benzopyrano-[ 3 ,2-(: pyridines, useful as sedatives and antiphlogistics in warm-blooded animals.

.4 Claims, No Drawings of l,2,3,4,4a, l a-hexahydro-( l 0H)- 1 -benzopyrano- [3,2-c1-pyridines, as well as to various. methods of preparing these compounds.

More particularly, the present invention relates to compounds of the formula wherein R, is straight or branched chain lower alkyl, lower alkenyl, lower alkinyl, cyclopropyl-lower alkyl, aral- .kyl, lower aliphatic acyl (such as acetyl), or

' araliphatic acyl (such as B-p'henylacetyl),

R and R which may be identical to ordifferent from, each other, are each hydrogen, halogen, lower alkylor lower alkoxy, and R, is hydrogen or lower alkyl.

The compounds according to the present invention may be prepared by a number of different methods involving well known chemical principles, among which the following have proved to be particularly efficient and convenient:

METHODA For the preparation of a compound of the formula I wherein R is hydrogen, by reacting a 4-basic substitutedl ,2,3,6-tetrahydro-pyridine of the formula (III) wherein R and R have the same meanings as in formula l and R, and R have the same meanings as informu- Most advantageously, equimolar amounts of compounds II and III are provided for the reaction, and it is preferably carried out in the presence of an inert organic solvent and at temperatures between 100 and 200C. in an inert gas atmosphere, followed by heating with an' inorganic 'ororganic acid and subsequent neutralization of the reaction mixture, whereupon the reaction product precipitates out. Examples of suitable inert organic solvents are benzene, chlorobenzene, toluene, ethylacetate and dibutylether.

METHOD B By reacting a l,2,3,4,4a,l0a-hexahydro-(l0H)-lbenzopyrano-[3,2-cl-pyridine of the formula wherein R and R have the same meanings as in formula 1, with a compound of the formula RIX (v) wherein R, has the sametmeanings as in formula I and 'X is the radical of a reactive ester, such as halogen, aro

of an inert organic solvent, suchas acetone, ethanol-or g benzene, 'at temperaturesup to the boiling point of the particular solvent which is used, and in the presence of a base, if necessary.

If the compound of the formula V is an alkylating agent, the free hydroxyl group in the 4a-position may simultaneously be alkylated by providing a commensurate excess of compound V; thus, for example, the simultaneous alkylation of the hydroxyl group may be effected with a hydrogen halide-containing alcohol at temperatures around l0OC. in an autoclave.

In those instances where either of the above methods yields a compound of the formula I wherein R, is hydrogen, which is always the case with method A, the

' 4a-hydroxyl group may, if desired, be subsequently LII converted into a lower alkoxy group pursuant to customary procedures; examples of suitable alkylating agents are alkylhalides, alkylsulfates or hydrogen halide-containing solutions of the corresponding alcohols. The alkylation is advantageously carried out at temperatures around C. and under elevated pressure.

A compound of the formula ll, which is needed as a starting material for method A, may be prepared by react-ing a piperidone-4 of the formula wherein R, has the same meanings as in formula I, with a secondary amine of the formula mann, a-Aminoalkylierung, Verlag Chemie, Weinheim, Germany 1960).

A compound of the formula IV may be obtained by reacting a 4-basic substituted- 1 ,2,3,6- tetrahydropyridine of the formula ll, wherein R is a protective group for secondary amines, such as acyl, benzyl, carbobenzoxy or carbamoyl, with an oaminomethyl-phenol of the formula lll, and subsequently removing the protective group by well known methods, such as by acid hydrolysis or hydrogenation.

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below.

EXAMPLE I Preparation of 2-allyl-4a-hydroxy-6-methyll,2,3,4,4a, l a-hexahydro-( H )-benzopyrano-[3,2-c] -pyridine by method A 13.9 gm (0.1 mol) of N-allyl-piperidone-4 and 7.1 gm (0.1 mol) of pyrrolidine were dissolved in 100 cc of benzene, and the solution was boiled until substantially the calculated amount of water had been split off and collected, yielding a solution of l-allyl-4-pyrrolidinol,2,3,6-tetrahydro-pyridine in benzene. The solvent was distilled off, the residue was dissolved in 200 cc of chlorobenzene, 19.3 gm of 2-methyl-6-diethylaminomethylphenol were added thereto, and the mixture was heated for 16 hours on an oil bath l60-l65C.) while stirring and passing nitrogen through the vessel. Thereafter, the chlorobenzene was distilled off in vacuo, the residue was admixed with 150 cc of 2N hydrochloric acid, and the acid mixture was refluxed for 5 hours. Subsequently, the reaction solution was allowed to cool and was then neutralized with sodium hydroxide. An oily product separated out, which slowly crystallized upon standing. Additional reaction product was recovered from the aqueous phase by ether extraction. 14 gm (54 percent of theory) of 2-allyl-4a-hydroxy-6-methyl-l,2,3,4,4a,l0a-hexahydro-(10H)- benzopyrano-[3,2-c1-pyridine, m. p. 99l0lC. (recrystallized from acetone), of the formula N-CHr- 0 11:0 H:

OH: OH

were obtained.

EXAMPLEZ Preparation of 2-propargyl-4a-hydroxy-6-methyllowed to cool and was then made alkaline with a saturated aqueous solution of sodium bicarbonate. The alkaline mixture was extracted with chloroform, the extract solution was dried over sodium sulfate, and the chloroform was evaporated, leaving an oily residue which crystallized upon treatment with petroleum ether. 5 gm (23 percent of theory) of 4a-hydroxy-6- methyl-1,2,3,4,4a,l0a-hexahydro-( 10H)- 1 benzopyrano-[3,2-c]-pyridine, m. p. l30-l32C. (recrystallized from ethylacetate), were obtained.

b. 2-Propargyl-4a-hydroxy-6-methyl-l ,2,3,4,4a,! 0ahexahydro-( l0H)-benzopyrano-[3,2-cl-pyridine A mixture of 21.9 gm (0.] mol) of 4a-hydroxy-6- methyl- 1 ,2,3,4,4a, l 0a-hexahydro-( lOH)-lbenzopyrano-[3,2-c]-pyridine, 20.8 gm (0.15 mol) of potassium carbonate, 250 cc of acetone and 14.3 gm (0.12 mol) of propargyl bromide was stirred and refluxed for 20 hours. Thereafter, the potassi-um salts formed by the reaction were filtered off and the acetone was distilled out of the filtrate in vacuo, leaving an oily residue which crystallized upon addition of methanol. 18.5 gm (72 percent of theory) of 2-propargyl-4a-hydroxy-6-methyl-l,2,3,4,4a,10a-hexahydro- (l0H)-l-benzopyrano-[3,2-cl-pyridine, m. p. ll2-ll 4C. (recrystallized from methanol), of the formula N-CHr-CEGH were obtained.

EXAMPLE 3 Preparation of 2-allyl-4a-methoxy-6-methyll,2,3,4,4a, l 0a-hexahydro-( lOH l -benzopyrano-[ 3 ,2- c]-pyridine by methylation of corresponding 4ahydroxy compound 20 gm (0.077 mol) of 2-allyl-4a-hydroxy-6-methyll,2,3,4,4a, l Oa-hexahydro-( 10H l -benzopyrano-[ 3 ,2- c]-pyridine were added to 600 cc of methanolic 2 percent hydrochloric acid, and the mixture was heated for 5 hours at C. in an autoclave. Thereafter, the reaction mixture was made alkaline with 2N sodium hydroxide and then extracted with ether. The ether was distilled out of the extract solution, leaving 16 gm of an oily residue which was chromatographically separated in a silicagel column. Two isomeric forms of 2-allyl-4amethoxy--methyll ,2,3,4,4a, l 0a-hexahydro-( 10H)- 1 benzopyrano-[3,2-c]-pyridine were obtained, namely: 2 gm (9.5 percent of theory) of one isomer whose hydrochloride had a melting point of 21 3-2 15C., and 4.5 gm (2L5 percent of theory) of another isomer whose hydrochloride had a melting point of 206-208 C., both recrystallized from methyl ethyl ketone.

EXAMPLE 4 Using a procedure analogous to that described in Example l, 38 percent of theory of 2-(B-phenyl-ethyl)-4ahydroxy-8-methyl- 1 ,2,3 ,4,4a, l 0a-hexahydro-( 10H l benzopyrano-[3,2-c]-pyridine, m. p. 13 l-l 33C. (recrystallized from isopropanol), of the formula were obtained from l-(B-phenyl-ethyl)-4-pyrrolidinol,2,3,6-tetrahydro-pyridine [prepared by reacting equimolar amounts of B-phenylethyl-piperidone-(4) and pyrrolidine] and 4 methyl-6- dimethylarriinomethyl-phenol.

EXAMPLE 5 Using a procedure analogous to that described in Example l, 39 percent of theory of 2-(B-phenyl-ethyl)-4ahydroxy-7-methyll ,2,3,4,4a, l 0a-hexahydro-( H)- 1 benzopyrano-[3,2-cl-pyridine, m. p. l40-l 43C. (recrystallized from ethanol), of the formula I N were obtained from l-(B-phenyl-ethyl)4 pyrrolidinol,2,3,6-tetrahydro-pyridine- [prepared by reacting equimolar amounts of B-phenylethyl-piperidone-(4) and pyrrolidine] and 3-methyl-6- dimethylaminomethyl-phenol.

' EXAMPLE6 Using a procedure analogous to that described in EX- ample l, 25 percent of theory of 2-(B-phenyl-ethyl) 4ahydroxy-6-methoxy-l ,2,3,4,4a, l Oa-hexahydro-( 10H l-benzopyrano-[3,Z-CI-pyridine, m. p. 8587 C. (recrystallized from ethylacetate), of the formula N-CHa-CHr-CqH \0/ were obtained from l-(fi-phenyl-ethyl)-4-pyrrolidinol,2,3,6-tetrahydro-pyridine [prepared by reacting equimolar amounts of B-phenylethyl-piperidone-(4) and pyrrolidine] and 2-methoxy-6- dimethylaminomethyl-phenol.

EXAMPLE 7 Using a procedure analogous to that described in Example l, 29 percent of theory of 2-(B-phenyl-ethyD-4ahydroxy-S-methoxyl ,2,3,4,4a, l 0a-hexahydro-( 10H l-benzopyrano-[3,2-cl-pyridine, m. p. l27-129C.-

(recrystallized from ethylacetate), of the formula were obtained from l-(B-phenyl-ethyl)-4-pyrrolidinol,2,3,6-tetrahydro-pyridine [prepared by reacting equimolar amounts of B-phenylethyl-piperidone-(4) and pyrrolidine] and 4-methoxy-6- dimethylaminomethyl-phenol.

EXAMPLE Using a procedure analogous to that described in Ex- "ample l, 25 percent of theory of 2-(B-phenyl-ethyl)-4a- EXAMPLE 9 Using a procedure analogous to that described in Example 22 percent of theory of 2-(B-phenyl-ethyl)-4ahydroxy-8-chlorol ,2,3,4,4a, l 0a-hexahydro-( 10H l benzopyrano-[ 3,2-cl-pyridine, m. p. 152- 1 54C. (recrystallized from methyl ethyl ketone), of the formula were obtained from l-(B-phenyl-ethyl)-4-pyrrolidinol,2 ,3,6-tetrahydro-pyridine [prepared by reacting equimolar amounts of ,8-phenyIethyl-piperidone-(4).

and pyrrolidine] methyl-phenol.

and 4-chloro-6-dimethylamino- EXAMPLE l0 9 Using a procedure analogous to that described in Ex .ample l, 12 percent of theory of 2-(B-phenyl-ethyl)-4ahydroxy-7,9-dimethyl-l ,2,3,4,4a, l Oa-hexahydro- (l0H)-l-benzopyrano-[3,2-c]-pyridine, m. p. 206-20 9C. (recrystallized from iso-propanol), of the formula N-CHr-CHz-CeHa Hie o were obtained from l-(B-phenyl-ethyl)-4-pyrrolidinol,2,3,6-tetrahydro-pyridine [prepared by reacting equimolar amounts of B-phenylethyl-piperidone-(4) and pyrrolidine] and 3,5-dimethyl-6- diethylaminomethyl-phenol.

EXAMPLE ll Using a procedure analogous to that described in Example l, 49 percent of theory of 2,8-dimethyl-4ahydroxy-l ,2,3,4,4a, l 0a-hexahydro-( 10H l benzopyrano-[3,2-c]-pyridine, m. p. l55l57C. (recrystallized from methyl ethyl 'ketone), of the formula were obtained from l-methyl-4-pyrrolidino-l,2,3,6- tetrahydro-pyridine [prepared by reacting equimolar amounts of N-methyl-piperidone-(4) and pyrrolidine] and 4-methyl-6-dimethylaminomethyl-phenol.

EXAMPLE 12 Using a procedure analogous to that described in Example l, 23 percent of theory of 2,7-dimethyl-4ahydroxyl ,2,3,4,4a, l Oa-hexahydro-( H)- 1 benzopyrano-[3,2-c]-pyridine, m. p. l39-l4lC. (recrystallized from methyl ethyl ketone), of the formu a N-CHa were obtained from l-methyl-4-pyrrolidino-l,2,3,6- tetrahydropyridine [prepared by reacting equimolar amounts of N-methyl-piperidone-(4) and pyrrolidine] and 3-methyl-6-dimethylaminomethyl-phenol.

EXAMPLE 13- EXAMPLE l4 Using a procedure analogous to that described in Example l, 26 percent of theory of 2-methyl-4a-hydroxy- S-methoxy-l ,2,3,4,4a,l0a-hexahydro-( l0H)-lbenzopyrano-l3,2-c]-pyridine, m. p. l45-l47C. (recrystallized from methyl ethyl ketone) were obtained from l-methyl-4-pyrrolidino-l ,2,3,6-tetrahydropyridine [prepared by reacting equimolar amounts of N-methyl-piperidone-(4) and pyrrolidine] and 4- methoxy-6-dimethylaminomethyl-phenol.

EXAMPLE 15 Using a procedure analogous to that described in Example 35 percent of theory of 2,7,9-trimethyl-4ahydroxyl ,2,3,4,4a,lOa-hexahydro-( l0l-l)-lbenzopyrano-[3,2-c]-pyridine, m. p. 206-208C. (recrystallized from methanol), of the formula N-CH;

BIG

2m were obtained from l-methyl-4-pyrrolidino-l ,2,3,6- tetrahydro-pyridine [prepared by reacting equimolar amounts of N-methyl-piperidone-(4) and pyrrolidine] and 3,S-dimethyl-6-diethylaminomethyl-phenol.

EXAMPLE 16 Using a procedure analogous to that described in Example l, 27 percent of theory of 2-allyl-4a-hydroxy-8- methyl- 1 ,2,3,4,4a, l 0a-hexahydro-( l0l-l)- l benzopyrano-[3,2-c]-pyridine, m. p. l l51 16C. (recrystallized from methyl ethyl ketone) were ob- 8 tained from l-allyl-4-pyrrolidino-l,2,3,6-tetrahydropyridine [prepared by reacting equimolar amounts of N-allyl-piperidone-(4) and pyrrolidine] and 4-methyl- 6-dimethylaminomethyl-phenol.

EXAMPLE 17 Using a procedure analogous to that described in Example l, 27 percent of theory of 2-allyl-4a-hydroxy-7- methyl- 1 ,2,3,4,4a, l Oa-hexahydro-( 10H l benzopyrano-[3,2-c1-pyridine, m. p. l l l-l l3C. (recrystallized from ethyl-acetate) were obtained from l-allyl-4-pyrrolidino-l ,2,3,6-tetrahydro-pyridine [prepared by reacting equimolar amounts of N-allylpiperidone-(4) and pyrrolidine] and 3-methyl-6- dimethylaminomethyl-phenol.

EXAMPLE 18 Using a procedure analogous to that described in Example 25 percent of theory of 2-allyl-4a-hydroxy-8- chloro-l ,2,3,4,4a, l 0a-hexahydro-( 10H l benzopyrano-[3,2-c1-pyridine, m. p. 205-208C. (recrystallized from methanol) were obtained from allyl-4-pyrrolidinol ,2,3 ,6-tetrahydro-pyridine [prepared by reacting equimolar amounts of N-allylpiperidone-(4) and pyrrolidine] and 4-chloro-6- dimethylaminomethyl-phenol.

EXAMPLE l9 Using a procedure analogous to that described in Example 1, 16 percent of theory of 2-ullyl-4a-hydroxy-6- methoxyl ,2,3,4,4a, l0a-hexahydro-( lOH l benzopyrano-[3,2-c]-pyridine, m. p. 200-202C. (recrystallized from isopropanol) were obtained from l-allyl-4-pyrrolidino-l ,2,3,6-tetrahydro-pyridine [prepared by reacting equimolar amounts of N-allylpiperidone-(4) and pyrrolidine] and 2-methoxy-6- dimethylaminomethyl-phenol.

EXAMPLE 20 Using a procedure analogous to that described in Example l, l3 percent of theory of 2-allyl-4a-hydroxy-8- methoxyl ,2,3,4,4a, l 0a-hexahydro-( lOH l benzopyrano-[3,2-c1-pyridine, m. p. 2092l 1C. (recrystallized from isopropanol) were obtained from l-allyl-4-pyrrolidinol ,2,3 ,6-tetrahydropyridine [prepared by reacting equimolar amounts of N-allylpiperidone-(4) and pyrrolidine] and 4-methoxy-6- dimethylaminomethyl-phenol.

EXAMPLE 21 Using a procedure analogous to that described in Example l, l6 percent of theory of 2-allyl-4a-hydroxy-7,9 -dimethyll ,2,3,4,4a,l0a-hexahydro-( l0H)-lbenzopyrano-[3,2-c]-pyridine, m. p. l92-l94C. (recrystallized from ethanol) were obtained from 1- allyl-4-pyrrolidinol ,2,3 ,6-tetrahydropyridine [prepared by reacting equimolar amounts of N-allylpiperidone-(4) and pyrrolidine] and 3,5-dimethyl-6- diethylaminomethyl-phenol.

EXAMPLE 22 Using a procedure analogous to that described in Example l, 50 percent of theory of 2-allyl-4a-hydroxyl,2,3,4,4a, l Oa-hexahydro-( l0H)-l-benzopyrano-[3 ,2-

cl-pyridine, m. p. 2l2-2l4C. (recrystallized from methanol) were obtained from l-allyl-4-pyrrolidinol,2,3,6-tetrahydropyridine [prepared by reacting equimolar amounts of N-allylpiperidone-(4) and pyrrolidine] and 6-dimethylaminomethylphenol.

' EXAMPLE 23 Using a procedure analogous to that describedin Example l, 8 percent of theory of 2-(y,y-dimethylallyl)- 4a-hydroxy-6-methyll ,2,3 ,4,4a, l a-hexahydro- (l0l-l)-l-benzopyrano-[3,2-c]-pyridine, m. p. ll8-l2 0C. (recrystallized from methylethyl ketone), of the formula- E AMPLE 24 Using a procedure analogous to that described in Example l, 39 percent of theory of 2-cyclopropylmethyl- 4a-hydroxy-6-methyll ,2,3,4,4a, l 0a-hexahydro-( l0 H)-l-benzopyrano-[3,2-cl-pyridine, m. p. 240-242C. (recrystallized from methanol), of the formula were obtained from, l-cyclopropylmethyl-4-pyrrolidinol ,2,3,6-tetrahydro-pyridine [prepared by reacting equimolar amounts of N-cyclopropylmethylpiperidone-(4) and pyrrolidine] and 2-methyl-6- dimethylaminomethyl-phenol. 1

EXAMPLE 25 Preparation of 2,8-dimethyl-4a-hydroxy-l,2,3,4,4 a, l 0a-hexahydro-( l0l-l)-l-benzopyrano-[ 3,2-c1- pyridine by method B 1.0 gm of 4a-hydroxy-8-methyl-l,2,3,4,4a,l0a-hexahydro-( 10H l -benzopyrano-[ 3,2-cl-pyridine was dissolved in 25 cc of acetone, and the solution was stirred at room temperature for 6hours together with gm of potassium carbonate and 0.6 gm methyliodide. The reaction product, 2,8-dimethyl-4ahydroxyl ,2,3,4,4 a, l 0a-hexahydro-( 10H l beniopyrano-[3,2-cl-pyridine, m. p. l55-l57C., was separated from unreacted starting material by columnchromatography with silieagelG/methanol. The yield was about 50 percent of theory.

EXAMPLE 26 Preparation of 2-allyl-4a-hydroxy-6-methyll,2,3,4,4a, l 0a-hexahydro-( 10H l -benzopyrano-[ 3,2- c]pyridine'by method B [prepared by 1.0 gm of 4a-hydroxy-6-methyl-l,2,3,4,4a,l0a-hexahydro-( 10H l -benzopyrano-[ 3,2-.c]-pyridine was dissolved in 25 cc of acetone, and the solution was stirred for six hours at room temperature together with 1.1 gm of potassium carbonate and 0.5 gm of allyl bromide. The reaction product, 2-allyl-4a-hydroxy-6- methyl- 1 ,2,3,4,4a, l0a-hexahydro-( 10H )-lbenzopyrano-l3,2-a]-pyridine, m. p. 99-l0lC. (recrystallized from acetone), was separated from unreacted starting material by column-chromatography with silicagel-G/methanol. The yield was about 60 percent of theory.

The compounds according to the present invention, that is, those embraced by formula 1 above, have useful pharmacodynamic properties. More particularly, they exhibit antiphlogistic and sedative activities in warmblooded animals, such as mice and rats, as evidenced by the following pharmacological tests:

SEDATlVE ACTIVITY The sedative activity was determined on mice in accordance with the standard test method described by Dews in Brit. J. Pharmacol. 8, 46(1953), which measures the inhibiting effect of the compound under investigation upon the spontaneous motility of the test animals. Adult male laboratory mice of the NMRlstrain with an average body weight of 20 gm were used. The compound under investigation or, in the case of the controls, the corresponding amount ofthe inert liquid vehicle, was administered 60 minutes prior to the beginning of the measurement of the spontaneous motility by means of an esophageal sound to groups of 10 animals per dose. The spontaneous motility of the mice was measured over a period of 30 minutes. At least three dosage levels were tested for each compound. From the percentage decrease in the motility after administration of the various dosages as against the control animals, the dose which produced a 50 percent inhibition of the spontaneous motility (ED was determined for each compound by graphic extrapolation.

ANTIPHLOGISTIC ACTIVITY The antiphlogistic activity was determined as a function of the anti-exudative effect against the carrageenin-edema or kaolin-edema induced in the rat paw, using the standard test methods described by Hillebrecht in Arzneimittel-Forschung 4, 607 (1954), and Winter in Proc. Soc. exp. Biol. Med 111, 544 (1962). The kaolin-edema was artificially induced by means of a subplantar injection of 0.05 cc of a 10 percent suspension of kaolin in an aqueous 0.85 percent solution of sodium chloride; similarly, the carrageeninedema was induced by subplantar injection of 0.05 cc of a 1 percent solution of carrageenin in an aqueous 0.85 percent sodium chloride solution. The degree of swelling in the rats paw was measured by means of the technique described by Doepfuer and Cerletti in Int. Arch. Allergy lmmunol. 12, 89 (1958). The test animals were adult male laboratory rats of the FW 49- strain having an average body weight of gm.

The compound under investigation was administered to the test animals perorally by means of an esophageal sound as an intimate mixture with methylcellulose. At least 10 .animals were used per dose for each compound. The controls received an equal volume of only the methylcellulose used as a vehicle. Each compound was tested at least at three dosage levels and was administered 30 minutes before inducing the kaolinedema or 60 minutes before inducing the carrageeninedema, respectively. Five hours after inducing the kaolin-edema or 3 hours after inducing the carrageenin-edema the measurement of the degree of swelling was made which was used as a basis for evaluation of the anti-exudative effect. The median values obtained from the treated animals were compared with those obtained from the control group, and by graphic extrapolation the dose was determined which produces a 35 percent reduction of the swelling (ED ACUTE TOXICITY The acute toxicity of the compounds under investigation was determined by oral administration to adult male laboratory mice of the NMRl-strain having an average body weight of 20 gm or to adult male laboratory rats of the FW 49-strain having an average body weight of 135 gm. The compounds were administered by means of an esophageal sound as an intimate mixture with methylcellulose. At least ten animals were used per dose.

The calculation of the dose which caused 50 percent of the animals to perish within seven days after administration thereof (LD was carried out pursuant to Litchfield and Wilcoxon (J. Pharmacol. exper. Therap. 96, 99 [1949]).

The following table shows the results obtained.

Sedative Activity in the mouse ED, in mg/kg p.o.

Acute Toxicity Compound 2,8-Dimethyl-4ahydroxyl,2,3,4,4a,l0ahexahydro-( H )-lbenzopyrano-[3,2-c l-pyridine (Example I 15.6 550 2-(2-Phenylethyl)-4ahydroxy-8-methyll,2,3,4,4a,l0flhexahydro-( l0l-l)-lbenzopyrano-l 3,2- cl-pyridine (Example 4) 2-Allyl-4a-hydroxy-6- methyl- 1,2,3,4,4a.10ahexahydro-( 10H )-1- benzopyrano-l3,2- cl-pyridine (Example 1) 2-Propargyl-4ahydroxy-6-methy1- l,2,3,4,4a,10 a hexahydro-( l0H)-lbenzopyrano-[3,2- cl-pyridine (Example 26) 4a-Hydroxy-6-mcthyl- 1,2,3,4,4a,10ahexahydro-( l0H)-lbenzopyrano[3,2-c l-pyridine (Example 2a) For pharmaceutical purposes the compounds according to the present invention are administered to warm-blooded animals perorally or parenterally as active ingredients in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such as tablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories and the like. One effective dosage unit of the compounds according to the present invention is from 0.83 to 5.0 mgm/kg body weight.

The following examples illustrate a few dosage unit compositions comprising a compound of the instant invention as an active ingredient and represent the best mode contemplated of putting the invention to practical use. The parts are parts byweight unless otherwise specified.

EXAMPLE 27 Tablets The tablet composition was compounded from the following ingredients:

l-benzopyrano-[3.2-cl-pyridine 250.0 parts Secondary calcium phosphate 230.0 parts Corn starch 200.0 parts Gelatin 10.0 parts Carboxymethyl cellulose, high viscosity 5.0 parts Magnesium stearate 5.0 parts Total 700.0 parts Compounding Procedure The benzopyranopyridine compound was intimately admixed with the calcium phosphate and the corn starch, the mixture was moistened with an aqueous 7.5:

EXAMPLE 28 Coated Pills The pill core composition was compounded from the following ingredients:

l-bcnzopyrano-[3,2-cl-pyridinc 100.0 parts Lactose 128.0 parts Cellulose, microcrystalline 60.0 parts Polyvinylpyrrolidone 8.0 parts Magnesium stearate 4.0 parts Total 300.0 parts Compounding Procedure The benzopyranopyridine compound was intimately admixed with the lactose and the cellulose, the mixture was moistened with an aqueous 7.5 percent solution of the polyvinylpyrrolidone, the moist mass was forced 13 through a l.5 mm-mesh screen, the granulate thus obtained was dried at 45C. and again passed through the screen. The dry granulate was admixed with the magnesium stearate, andthe mixture was pressed into 300 mgm-pill cores which were then coated with a thin shell consisting essentially of sugar and talcum and finally polished with beeswax. Each coated pill contained 100 mgm of the benzopyranopyridine compound and, when administered perorally to a warm-blooded animal of about 60 kg body weight in need of such treatment, produced very good antiphlogistic effects.

EXAMPLE 29 Suppositories v The suppository composition was compounded from the following ingredients:

pyridine j 300 parts Cocoa butter I460 parts Total i760 parts Compounding Procedure The finely pulverized benzopyranopyridine. compound was stirred, with the aid of an immersion homogenizer, into the cocoa butter which had been melted and cooled to 40C. The mixture was cooled to 37C. and was then poured into cooled suppository molds, each holding 1,760 mgm of the mixture. Each suppository contained 300 mgm of the benzopyranopyridine compound and, when administered by the rectal route to a warm-blooded animal of about 60 kg body weight in need of such treatment, produced very good sedative effects.

EXAMPLE 30 Suspension The suspension was compounded from the following ingredients:

l-benzopyrano-[3,2-c]-pyridine 4.0 parts Methylcellulose l.0 parts Colloidal silicic acid 0.5 parts Sorbitol l0.0 parts Sodium cyclamate 0.2 parts Polyethylene sorbitan monooleate 0.1 parts Benzoic acid 0.l parts Caramel flavoring 0.l parts Distilled water 89.0 parts Total 105.0 parts Compounding procedure The methylcellulose was dissolved in about one-third of the indicated amount of distilled water while vigorously stirring. The remaining distilled water was heated to 70C., and the benzoic acid, the sorbitol and the polyethylene sorbitan monooleate were dissolved therein. The resulting solution was cooled to room temperature, the sodium cyclamate was dissolved therein, and then the-benzopyranopyridine and the colloidal silicic acid were successively suspended in the solution with the aid of an immersion homogenizer. The resulting suspension was added to the aqueous methylcellulose solution while stirring, and the mixture was again homogenized. Finally, the caramel flavoring was added. 5 cc of the finished suspension contained 200 mgm of the benzopyranopyridine compound and, when administered perorally to a warm-blooded animal of about 60 kg body weight in need of such treatment, produced very good antiphlogistic effects.

EXAMPLE 3l Hypodermic Solution The solution was compounded from the following ingredients:

l Allyl-4a-hydroxy-6-methyll-benzopyrano-l 3,2-cI-pyridine l0,0.0 parts lN hydrochloric acid and pH 2.7 400.0 parts by vol.

Sorbitol l00.0 parts Distilled water q.s.ad 5000.0 parts by vol.

Compounding Procedure The benzopyranopyridine compound. and the sorbitol were dissolved in a' sufficient amount of the distilled water acidified with the hydrochloric acid.

Thereafter, the solution was diluted with additional distilled water to the indicated volume and filtered until free from suspended'particles. The filtrate was filled into white 5 cc-ampules, which were sealed and then sterilized at l20C. for 20 minutes. Each ampule contained 100 mgm of the benzopyranopyridine compound, and when the contents thereof were administered by intramuscular injection to a warmblooded animal of about 60 kg body weight in need of such treatment, very good antiphlogistic effects were produced.

EXAMPLE 32 Syrup The syrup was compounded from the following ingredients:

2,8-Dimethyl-4a-hydroxy- .2.3 .4,4a, l 0a-hexahydro-( 10H benzopyranopyridine compound, the food color, the polyvinylpyrrolidone and the sorbitol were successively dissolved therein. The resulting solution was cooled to room temperature, and the glycerin and the flavoring were added thereto. 5 cc of the finished syrup contained mgm of the benzopyranopyridine compound and, when administered perorally to a warm-blooded animal of about 60 kg body weight in need of such treatment, produced very good sedative effects.

Although the above dosage unit composition examples illustrate only a few compounds of the present invention as active ingredients, it should be understood that any other compound embraced by formula I may be substituted for the particular benzopyranopyridine compound in Examples 27 through 32. Moreover, the amount of active ingredient in these examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements. In addition, a dosage unit composition according to the present invention may also comprise one or more other active ingredients having the same spectrum of activity or other spectra of activity.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodi- 

2. 2-propargyl-4a-hydroxy-6-methyl-1,2,3,4,4a,10a-hexahydro-(10H)-1 -benzopyrano(3,2-c)pyridine.
 3. 2-cyclopropylmethyl-4a-hydroxy-6-methyl-1,2,3,4,4a,10a-hexahydro-(10H)-1 -benzopyrano(3,2-c)pyridine.
 4. 2-( Beta -phenethyl)-4a-hydroxy-8-methyl-1,2,3,4,4a,10a-hexahydro-(10H)-1 -benzopyrano(3,2-c)pyridine. 